Alkamine esters of delta-cyclopentenyl-delta 2-cyclohexenylacetic acid



Patented Jan. 23, 1951 .ALKAMINEE STERS OF A?.- GCLORENTENYL- ACYCIIOHEXENYLAGETIC 1 ACID Robert Bruce Mofliett, Kalamazoo, Mich, and

Charlotte Anne Hart, Kansas' City, Mo., assignors to; George A..Breonand Company, Kansas City, Mo.,. a. corporation ofyMissouri:

No-Drawing; Application .A-ngustlO, 194.8, Serial No. 4354i.

: 8, Claims. (01. zoo -2943') This. invention relatesto aminoalkyl.esters of -A cyclopentenylM-cyclohexenylaceticacids and totherapeutically acceptable salts thereof which are useful asantispasmodic agents. This. is a oontinuation in-partofour co-pendingapplica- 7 .tion,, S; N-. 639,405,. filed January 5,. 1946, nowabandoned. These estershave-the formula diethyl'amino, dipropylamino,d'i-butylamino, but'yl'propylamino, piperidyl, Z methyIpipEridyI,morpholinyl, thiomorph-olinyl, beta-hydroxyethylethylamino, etc. Thesemaybe classed together. as. aliphatic tertiary-amino groups, the

heterocyclic' rings are distinctly non-aromatic in character and can bethought of as two alkyl groups joined together by a divalent bridge suchas -Cl-I2-, -O- or --S.

2' methyl sulfate; methylbenzenesulfonate, methyl p-toluenesulfonate,etc.

"Synthetic antispasmodics usuallyhave both amusculotropic(papaverine-like) neurotropic (athropine-like) action. It' is desirablethat new compounds be introduced which have high neurotropic activitybutwhich lack the characteristic undesirable physiological sideeffects ofatropine.

Our compounds are distinguished by high neurotropic activity, and,. inadditiomseveral members of'the seriesshow antihistaminic. action.

. ,These compounds 'are generally used in the .form. of. water-solubleacid-addition salts or quaternary ammonium derivatives. The acids which.may be used to prepare the salts are those .hich produce, whencombinedwith the basic esters, salts whose anions are relativelyinnocuous to the animal organism. in therapeutic doses of the salts, sothat the beneficial physiological properties inherent in the basicesters are not vitiated by side-effects ascribable to theanions.Appropriate acid addition salts are those derived from; mineral acids.such: as hydrochloric. acid,

,hydrobromic acid, hydriodi'c, acid, and? sulfuric acidiandorganic acidssuch as acetic acid; citric acidandtartaric. acid. Thequaternaryammonium derivatives are obtained by the addition of alkyl oraralkyl esters of' inorganic acids or organic .sulfonic. acids, such. as.methyl' chloride,

methyl bromide, methyl iodide, ethyl" bromide, propyl chloride, benzylchloride," benzyl bromide,

Our compounds areconveniently prepared .by-

esterification of M-cyclopentenyl-A -cyclohexa nyl aceticacid with anamino alcohol. The acid itself may be prepared by successivealkylationsof diethyl malonate or ethyl cyanoacetate with a A-cyclopentenyl halide and a, A -cyc1ohexeny1 halide, followed byhydrolysis and decarboxyla- ,tion of the disubstituted malonic orcyanoacetic esters to A -cyclopentenyl-A -cyclohexenylacetic acid. Thepreferred method involves alkylation of diethyl A cyclopentenylma'lonatewith 1,2-dibromocyclohexane to give directly diethyl A -cyclopenteny1-A-cyclohexenylmalonate. The expected simple alkylation product of thisreaction, diethyl A -cyclopentenyl-2-zbromocyclohexylmalonate, is notisolated, hydrogen bromide being split out under the reaction conditionsused to give the desired 2-3' double bond in the cyclon'exane ring. Thesubstituted malonio ester is hydrolyzed to the manolic acid by heatingunder pressure with a potassium hydroxide solution. Further heatingunder normal pressure causes elimination of one carboxyl group from the'malonic' acid to give A -cyclopentenyleA -cyclohexenylacetic acid.

The compounds of our invention, basic esters of A-cyclopentenylM-cyclohexenylacetic acid, and their acid addition saltsare prepared by one of the-following methods; v

(1) An acid halide or anhydride of A -cycloc- :pentenyl-Acyclohexenylacetic acid is. reacted with a tertiary-aminoalkanol' oftheformula.

atoms" and 'N= B 'isa tertiary amino: group. The reaction is effectedbysimple admixture; :of the" two components" although heatingisgenerally used to accelerate" the reaction. Thef'ree basic ester is'obtained by addition of alkali totheure'zaction mixture. The basic estermay be convertedto an acid addition .salt bysthez. addition,

prefer-abli -in non-aqueouszmedium;.zofia there:-

action and 3 peutically acceptable acid, such as hydrogen chloride inalcoholic solution.

(2) The A -cyclopenteny1-A -cyclohexenylacetic acid is reacted with atertiary-aminoalkanol using a mineral acid, such as sulfuric acid, as acatalyst, present in an amount greater than that necessary to neutralizethe amino alcohol. The free basic ester and its acid addition salts areobtained as in method (1) (3) The A -cyclopentenyl-A -cyclohexenylaceticacid is heated with a tertiary-aminoalkyl halide of the formula Z-YN=B,where Z is halogen (preferably chlorine or bromine) and Y and B have thesame meaning as before. The free basic ester and its acid addition saltsare obtained as in method 1).

(4) A metallic salt of A -cyclopentenyl-A -cyclohexenylacetic acid isheated or simply mixed with a tertiary-aminoalkyl halide. In this casethe free basic ester is formed directly.

Quaternary ammonium salts are prepared by mixing the free basic esterwith a lower alkyl or aralykyl ester of a strong inorganic acid ororganic sulfonic acid, preferably in an inert organic solvent such asbenzene or ether, with or without gentle heating. The salt eithercrystallizes immediately or can be obtained by concentration of thesolvent. 7

Example 1 (a) Diethyl A -cyclopentenyl-M-cyCloheazenylmalonate.To asolution of '74 g. of sodium in 1.2 liters in absolute ethanol is added271.2 g. of diethyl A -cyclopentenylmalonate. Most of the alcohol isdistilled OE and toluene is added and distilled ofi until the boilingpoint reached is about 110 C. Enough more dry toluene is added to bringthe volume to about 800 cc. and then 387.2 g. of 1,2-dibromocyclohexaneis added slowly. After refluxing for two hours the mixture is cooled,600 cc. of water is added and the layers are separated. The solvent isremoved and the product is distilled through an efficient column givingabout 202 g. (53.2%) of diethyl M-cyclopentenyl-A cyclohexenylmalonate,B. P. 124 C.

(b) A cyclopentenyl A cycloheccenylacetic acid.To a solution of 40 g. ofpotassium hydroxide in a 100 cc. of ethanol is added 40 g. of diethyl Acyclopentenyl-M- cyclohexenylmalonate. The mixture is placed in a bomband heated to a 140-160" C. for 3 hours. After cooling, the product isdissolved in one liter in water and extracted with ether. Acidificationof the aqueous layer gives an oil which is taken up in ether, washedwith Water and dried over anhydrous sodium sulfate. The ether is removedand the residue is heated to 180 C. until no more car- .bon dioxide isevolved. The residue is distilled in vacuo and the fraction thatdistills at 101 C. under 0.01 mm. pressure is collected, giving Acyclopentenyl A cyclohexenylacetic acid, n =l.5120; d4 =l.0600.

(c) Beta-die'thylaminoethyl M-cyclopentenyln -cycloherenylacetate andits hydrochloride.- A -cycIopentenyl-A -cyclohexenylacetic acid (22 g.)is neutralized with an alcoholic solution of sodium methoxide and 14.5g. of beta-diethylaminoethyl chloride in isopropyl alcohol is added. pThe mixture is refluxed from three to four hours,

the solution is cooled and ether added to precipitate the salts. Afterfiltration, the solvent is removed by vacuum disillation, and theresidue is distilled at 116 C. under 0.02 mm. pressure. Thedistillate istaken up in dry etherand the ester hydrochloride is precipitated by theaddition of anhydrous hydrogen chloride gas. The precipitatedhydrochloride of beta-diethylaminoethyl A -cyclopentenyl-A-cyclohexenylacetate is filtered and dried; M. P. 108ll0.5 C.

Example 2 (a) A cyclopentenyl A cyclohexenylacetyl chZoride.- A solutionof 41.2 g. (0.2 m.) of A -cyclopentenyl-A -cyclohexenylacetic acid and35.7 g. (0.3 m.) of thionyl chloride in 100 cc. of dry benzene isrefluxed for two and one-half hours. The solvent is removed bydistillation, more benzene added and again concentrated to insurecomplete removal of excess thionyl chloride. The residue is distilled atreduced pressure giving about 41 g. of A -cyclopentenyl-n-cyclohexenylacetyl chloride, B. P. 110 C. (0.3 mm.); n =1.5180; d4=l.0974.

(b) Beta- (N -pz'peridyl) -ethyl n -cyclopentenyZ-A -cyclohexenylacetateand its hydrochloride.A solution of 30 g. (0.134 m.) of A-cyclopentenyl-A -cyclohexenylacetyl chloride and 17.3 g. (0.134 m.) ofbeta-N-piperidylethanol in cc. of dry benzene is refluxed for fourhours. Some of the product crystallizes at this point as thehydrochloride and is filtered off after cooling. This hydrochloride isneutralized with sodium carbonate solution. The benzene filtrate isdiluted with ether and extracted with water and dilute hydrochloricacid; the aqueous extracts are neutralized with sodium carbonate andcombined with the other sodium carbonate solution obtained above. Thefree basic ester is extracted with ether which is then dried overanhydrous sodium sulfate and concentrated. The product distills at 139C. g. (59%) of beta-(N-piperidyD-ethyl A -cyclopentenyl-A-cyclohexenylacetate; m 1 .5070; dl =l.0222.

The hydrochloride is made in the usual manner. It precipitates fromether as fine crystals in about 94% yield, M. P. 133-142" C.

Example 3 Beta-dimethylamznoethyl M-cyclopentenyl-A2-cycloherenylacetate and its hydrochloride are prepared by methodspreviously described start,- ing with A -cyclopentenyl-A-cyclohexenylacetic acid and beta-dimethylaminoethanol. The free basicester boils at C. (0.05 mm.), n =l.4948,' d4 =1.00l2, and itshydrochloride has the M. P. 129-133.5 C.

Example 4 Z-dz'ethylamino-Z-propyl A -cyclopentenyl-Acycloheacenylacetate and its hydrochloride are prepared by methodspreviously described startingwith A -cyclopentenyl-A -cyc1ohexenylaceticacid and 1-diethylamino-Z-propanol. The free basic ester boils at 116 C.(0.03 mm.), n =1.l882; d4 =0.9786, and its hydrochloride has the M. P.1l8l20 C.

Example 5 I Beta- (N -morpholinyl) -et hyl A -cyclopentenyl-M-cyclohe11:ehylacetafe and its hydrochloride are prepared by methodspreviously described starting With A -cyclopentenyl-zl-cyclohexenylacetic acid and beta-(N-morpholinyl)-ethanol. free basicester boils at 130 C. (0.02 mm.), n .5083; d4 =1.0655, and itshydrochloride (0.07 mm.), giving about 25.1

The

Example 6 Gamma-diethylaminopropyl A cycZopantenyL n-cyclohexclnylaceiate and its hydrochloride are prepared by methodspreviously described starting with A -cyciopentenyl-A-cyc1ohexenylacetic acid and gamma-diethylaminopropanoi. The free basicester boils at 131 C. (0.07 mm.), n =1.4900; d4 =0.976'1, and itshydrochloride has the M. P. l15118 C.

We claim:

1. A substance of the group consisting of basic esters of the formulawherein Y is an alkylene bridge of 2-5 carbon atoms and N=B is atertiary-amino group of the class consisting of di-lower-alkyIamino,piperidyl and morpholinyl radicals; and acid ad.- dition and quaternaryammonium salts thereof.

2. A substance of the group consisting of basic esters of the formulawherein Y is an alkylene bridge of 2-5 carbon atoms and R and R arelower alkyl groups; and acid addition and quaternary ammonium saltsthereof.

3. A substance of the group consisting of basic esters of the formulaCH2CH2 CH2 CHrCz where Y is an alkylene bridge of 2-5 carbon atoms; andacid addition and quaternary ammonium salts thereof.

4. A substance of the group consisting of betadiethylaminoethyl A-cycl0penteny1-A -cyc1ohexenylacetate having the formula CH2CH3 and acidaddition and quaternary ammonium salts thereof.

5. A substance of the group consisting of beta- 6 (N piperidyl) ethylM-cyclopentenyl-A -cyclo hexenylacetate havingthe formula CHzCHz andacid addition and quaternary ammonium salts thereof.

6. A substance of the group consisting of betadimethylaminoalkyl Acyclopentenyl-M-cyclohexenylacetate having the formula and acid additionand quaternary ammonium salts thereof.

7. A substance of the group consisting of l-diethylamino 2 propyl Acyclopentenyl A cyclohexenylacetate having the formula and acid additionand quaternary ammonium salts thereof.

8. A substance of the group consisting of gamma-diethylaminopropyl A-cyclopentenyl-A cyclohexenylacetate having the formula CHzCHz and acidaddition and quaternary ammonium salts thereof.

ROBERT BRUCE MOFFETT. CHARLOTTE ANNE HART.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 1,677,123 Adams July 17, 19282,265,184 Miescher et a1. Dec. 19, 1941 2,351,833 Northey et al June 20,1944 2,417,208 Martin et al. Nov. 11, 1947 FOREIGN PATENTS NumberCountry Date 93,341 Sweden Nov. 19, 1938 532,943 Great Britain Feb. 4,1941 220,975 Switzerland Aug. 1, 1942 221,219 Switzerland Aug. 17, 1942221,519 Switzerland Sept. 1, 1942 Certificate of Correction Pateut N o.2,538,795

ROBERT BRUCE MOFFETT ET AL.

It ishereby certified that error appears in the printed specification ofthe above numbered patent requiring correction as follows:

Column 2, line 32, for manolio read malom'c; column 6, line 27, for -2propyl read -2-p7-0;03 Z; and that the said Letters Patent should beread as corrected above, so that the same may conform to the record ofthe case in the Patent Office.

Signed and sealed this 3rd day of April, A. D. 1951.

THOMAS F. MURPHY,

Assistant Commissioner of Patents.

January 23, 1951 i

1. A SUBSTANCE OF THE GROUP CONSISTING OF BASIC ESTERS OF THE FORMULA